International Journal of Pharmaceutics最新文献_第9页

PET biodistribution study of subcutaneous and intravenous administration of adalimumab in an inflammatory bowel disease model 炎症性肠病模型中皮下和静脉给药阿达木单抗的PET生物分布研究

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125011

Jessica Codesido , Lara García-Varela , Xurxo García-Otero , Sheila Bouzón-Barreiro , Noemí Gómez-Lado , Francisco José Toja-Camba , Cristina Mondelo-García , Héctor Lazaré , Julia Baguña Torres , Jana Vidal-Otero , Santiago Medin-Aguerre , Alejandro Sanchez-Crespo , Francisco J. Otero-Espinar , José R. Herance , Anxo Fernández-Ferreiro , Pablo Aguiar

Monoclonal antibodies targeting tumor necrosis factor-alpha (antiTNF-α) are used for patients with immuno-mediated illness as inflammatory bowel disease (IBD). However, 20–40 % of IBD patients do not respond to these therapies, and increasing knowledge of biodistribution could optimize their use and consequently their effectiveness. The aim of this study is to compare the biodistribution of adalimumab after intravenous (IV) and subcutaneous (SC) administration using Positron Emission Tomography (PET) imaging in IBD animal models. IBD was induced in mice using oral dextran sulfate sodium (DSS) and each induced animal was individually confirmed using [¹⁸F]FDG PET/CT scans, weight monitoring and histopathological analysis of colon tissue samples. The SC and IV biodistribution pharmacokinetics profiles and in vivo biodistribution of adalimumab labeled with ⁸⁹Zr were evaluated using a dedicated PET/CT scanner. Mean standardized uptake values (SUV) were estimated from the colon, liver, and blood over seven days. Blood analysis revealed faster elimination of adalimumab in IBD models compared to controls, and after IV compared to SC administration (SUV 168 h p.i. SC-IBD = 0.06 ± 0.02, SC-Control = 1.08 ± 0.11, IV-IBD = 0.02 ± 0.01, IV-Control = 0.26 ± 0.13). Furthermore, IBD models exhibited faster whole-body clearance than controls and an earlier and higher concentration peak of adalimumab in the colon after IV (SUV 6 h p.i. IBD-IV = 2.11 ± 0.18) compared to SC administration (SUV 24 h p.i. IBD-SC = 1.49 ± 0.27). Our findings demonstrate the significant influence of the administration route and the TNF-α expression (local and also systemic) on the amount of adalimumab reaching the colon over time.

针对肿瘤坏死因子-α (anti - tnf -α)的单克隆抗体用于炎症性肠病（IBD）等免疫介导性疾病的患者。然而，20- 40% %的IBD患者对这些疗法没有反应，增加对生物分布的了解可以优化它们的使用，从而提高它们的有效性。本研究的目的是利用正电子发射断层扫描（PET）在IBD动物模型中比较阿达木单抗在静脉（IV）和皮下（SC）给药后的生物分布。采用口服葡聚糖硫酸钠（DSS）诱导小鼠IBD，并通过[18F]FDG PET/CT扫描、体重监测和结肠组织样本的组织病理学分析对每只诱导动物进行单独确认。使用专用PET/CT扫描仪评估89Zr标记阿达木单抗的SC和IV生物分布、药代动力学特征和体内生物分布。平均标准化摄取值（SUV）估计从结肠，肝脏和血液超过7天。血液分析显示更快消除adalimumab在炎症性肠病模型相比,控制,和之后第四SC相比政府(SUV 168 h p。SC-IBD = 0.06 ±0.02 ,SC-Control =  1.08±0.11 ,IV-IBD = 0.02 ±0.01 ,IV-Control =  0.26±0.13 )。此外，与SC给药（SUV 24 h p.i. IBD-SC = 1.49 ± 0.27）相比，IBD模型比对照组表现出更快的全身清除率和更早更高的阿达利单抗在IV后结肠中的浓度峰值（SUV 6 h p.i. IBD-IV = 2.11 ± 0.18）。我们的研究结果表明，随着时间的推移，给药途径和TNF-α表达（局部和全身）对阿达木单抗到达结肠的量有显著影响。

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引用次数: 0

Development of axitinib-loaded polymeric ocular implants for the treatment of posterior ocular diseases 阿西替尼负载聚合物眼植入物治疗后眼疾病的进展。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125099

Febri Annuryanti , Masoud Adhami , Ubah Abdi , Juan-Dominguez Robles , Eneko Larrañeta , Lalitkumar K Vora , Thakur Raghu Raj Singh

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the primary causes of vision impairment and blindness worldwide. The current treatment for these diseases is an intravitreal injection of anti-VEGF agents, which are costly and require frequent injections. Implants can be used to sustain the release of drugs and minimize side effects. Axitinib (AX) is a potent VEGF receptor inhibitor and a promising candidate for treating posterior ocular diseases, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). A sustained release of AX was successfully achieved from 3D-printed AX-loaded implants fabricated using the well-known 3D printing technique, semi-solid extrusion (SSE). AX at concentrations of 10% w/w and 20% w/w was incorporated within the polycaprolactone (PCL) and Precirol®-based matrix. The fabricated implants were characterized via FTIR spectroscopy, SEM imaging, and thermal analysis. The implants were also evaluated for their drug release and biocompatibility. The AX-loaded implants exhibited thermal stability, and no chemical interactions were found between AX and the matrix components. The release mechanism study of AX revealed that the concentration of drug loading influenced AX release from the implant, with a 10% w/w and 20 %w/w of AX showing first-order and Korsmeyer-Peppas mechanism, respectively. A biocompatibility study using ARPE-19 cells confirmed that AX-loaded implants are nontoxic and safe for ocular use.

糖尿病视网膜病变（DR）和年龄相关性黄斑变性（AMD）是世界范围内视力损害和失明的主要原因。目前治疗这些疾病的方法是玻璃体内注射抗vegf药物，这是昂贵的，需要经常注射。植入物可以用来维持药物的释放并减少副作用。Axitinib （AX）是一种有效的VEGF受体抑制剂，是治疗后眼疾病（如糖尿病视网膜病变（DR）和年龄相关性黄斑变性（AMD））的有希望的候选药物。使用著名的3D打印技术半固态挤压（SSE）制造的3D打印AX负载植入物成功地实现了AX的持续释放。将浓度为10% w/w和20% w/w的AX掺入聚己内酯（PCL）和precrol®基基质中。通过FTIR光谱、SEM成像和热分析对制备的植入物进行了表征。同时对植入物的药物释放和生物相容性进行了评价。AX负载的植入物表现出热稳定性，并且没有发现AX与基质组分之间的化学相互作用。AX的释放机制研究发现，载药浓度影响AX从种植体的释放，10% w/w和20% w/w的AX分别表现为一级和Korsmeyer-Peppas机制。一项使用ARPE-19细胞的生物相容性研究证实，载ax植入物无毒且安全用于眼部。

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引用次数: 0

Clinically relevant cell culture model of inflammatory bowel diseases for identification of new therapeutic approaches 临床相关的炎症性肠病细胞培养模型，以确定新的治疗方法。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125062

Thomas Antoine , Arnaud Béduneau , Claire Chrétien , Raphaël Cornu , Francis Bonnefoy , Brice Moulari , Sylvain Perruche , Yann Pellequer

Inflammatory Bowel Diseases (IDB) are chronic disorders characterized by gut inflammation, mucosal damage, increased epithelial permeability and altered mucus layer. No accurate in vitro model exists to simulate these characteristics. In this context, drug development for IBD or intestinal inflammation requires in vivo evaluations to verify treatments efficacy. A new model with altered mucus layer composition; altered epithelial permeability and pro-inflammatory crosstalk between immune and epithelial cells will be developed to enhance in vitro models for studying IBD treatments. The effects of dextran sulfate sodium and/or lipopolysaccharides on intestinal permeability, cytokines synthesis (IL-6, IL-8, TNF-α and IL-1β), mucins (MUC2, MUC5AC) and tight junction proteins expression (Claudin-1, ZO-1 and Occludin) were investigated in a tri-coculture model combining differentiated Caco-2/HT29-MTX cells and THP-1 cells. Two anti-inflammatory agents were evaluated to assess the model’s therapeutic strategy applicability (corticoids and pro-resolving factors). Two in vitro models have been developed. The first model, characterized by increased permeability of the epithelial layer and subsequent secretion of inflammatory cytokines, can reproduce the different phases of inflammation, and enables the evaluation of preventive treatments. The second model simulates the acute phase of inflammation and allows for the assessment of curative treatments. Both models demonstrated reversibility when treated with betamethasone and pro-resolving factors. These in vitro models are valuable for selecting therapeutic agents prior to their application in in vivo models. They enable the assessment of agents’ anti-inflammatory effects and their ability to permeate the inflamed epithelial layer and interact with immune cells.

炎症性肠病（IDB）是以肠道炎症、粘膜损伤、上皮通透性增加和粘液层改变为特征的慢性疾病。目前还没有准确的体外模型来模拟这些特征。在这种情况下，开发治疗肠道疾病或肠道炎症的药物需要进行体内评估，以验证疗效。我们将开发一种具有粘液层组成改变、上皮细胞通透性改变以及免疫细胞和上皮细胞之间的促炎串扰的新模型，以增强研究 IBD 治疗方法的体外模型。在结合分化的 Caco-2/HT29-MTX 细胞和 THP-1 细胞的三层培养模型中，研究了葡聚糖硫酸钠和/或脂多糖对肠道通透性、细胞因子合成（IL-6、IL-8、TNF-α 和 IL-1β）、粘蛋白（MUC2、MUC5AC）和紧密连接蛋白表达（Claudin-1、ZO-1 和 Occludin）的影响。对两种抗炎药物进行了评估，以评估该模型的治疗策略适用性（皮质激素和促溶解因子）。已开发出两种体外模型。第一个模型的特点是上皮层通透性增加，随后分泌炎症细胞因子，可以再现炎症的不同阶段，并能对预防性治疗进行评估。第二个模型模拟炎症的急性期，可以评估治疗方法。在使用倍他米松和促溶解因子治疗时，这两种模型都表现出可逆性。这些体外模型对于在体内模型应用前选择治疗药物非常有价值。它们可以评估药物的抗炎效果及其渗透发炎上皮层并与免疫细胞相互作用的能力。

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引用次数: 0

Deposition simulations of realistic dosages in patient-specific airways with two- and four-way coupling 实际剂量的沉积模拟在病人特定的气道与二和四向耦合。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125019

Josh Williams , Jose Manuel Menendez Montes , Steve Cunningham , Uwe Wolfram , Ali Ozel

Inhalers spray over 100 million drug particles into the mouth, where a significant portion of the drug may deposit. Understanding how the complex interplay between particle and solid phases influence deposition is crucial for optimising treatments. Existing modelling studies neglect any effect of particle momentum on the fluid (one-way coupling), which may cause poor prediction of forces acting on particles. In this study, we simulate a realistic number of particles (up to 160 million) in a patient-specific geometry. We study the effect of momentum transfer from particles to the fluid (two-way coupling) and particle–particle interactions (four-way coupling) on deposition. We also explore the effect of tracking groups of particles (‘parcels’) to lower computational cost. Upper airway deposition fraction increased from 0.33 (one-way coupled) to 0.87 with two-way coupling and

10 µ m

particle diameter. Four-way coupling lowers upper airway deposition by approximately 10% at

100 µ g

dosages. We use parcel modelling to study deposition of

4 - 20 µ m

particles, observing significant influence of two-way coupling in each simulation. These results show that future studies should model realistic dosages for accurate prediction of deposition which may inform clinical decision-making.

吸入器将超过1亿个药物颗粒喷射到口腔中，其中很大一部分药物可能会沉积在口腔中。了解颗粒和固相之间复杂的相互作用如何影响沉积对于优化处理至关重要。现有的模型研究忽略了粒子动量对流体的任何影响（单向耦合），这可能导致对作用在粒子上的力的预测不佳。在这项研究中，我们在一个病人特定的几何形状中模拟了真实数量的粒子（高达1.6亿）。我们研究了从粒子到流体的动量传递（双向耦合）和粒子-粒子相互作用（四向耦合）对沉积的影响。我们还探讨了跟踪粒子群（“包裹”）的效果，以降低计算成本。上气道沉积分数从0.33（单向耦合）增加到0.87（双向耦合，颗粒直径为10µm）。在100µg剂量下，四向耦合可使上呼吸道沉积降低约10%。我们使用包裹模型来研究4-20µm颗粒的沉积，在每个模拟中观察到双向耦合的显著影响。这些结果表明，未来的研究应该模拟真实的剂量，以准确预测沉积，从而为临床决策提供信息。

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引用次数: 0

Targeting hyperactive mitochondria in activated HSCs and inhibition of liver fibrogenesis in mice using sorafenib complex micelles 索拉非尼复合胶束靶向活化造血干细胞中过度活跃的线粒体和抑制小鼠肝纤维化。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125058

Li Xiang , Yuting Qin , Lei Li , Xianjing Xiang , Wenhui Zhang , Qiangqiang Jiao , Yaru Shao , Xinqiong Huang , Meichun Wu , Tianle Zhou , Yukang Lin , Yuping Chen

Liver fibrosis is a pathological condition marked by the excessive buildup of extracellular matrix primarily resulting from the transformation of quiescent hepatic stellate cells (HSCs) to myofibroblastic (MF) phenotype and their resultant over-expansion. Activated HSCs completely rely on their hyperactive mitochondria to supply the energy and biomass for their rapid proliferation and collagen secretion, so an intervention targeting their mitochondria can effectively restrict their pathological amplification and contribution to liver fibrosis. Here we tried sorafenib, a drug that plays anticancer roles by inducing the disruption and loss of mitochondrial functions, to reach an antifibrotic goal. And a complex micellar system, VA-PEG-PCL/TPGS (VPP/TPGS), was specifically designed and fabricated to encapsulate and deliver sorafenib selectively to activated HSCs to overcome its application limitations in bioavailability, toxicity and intracellular stay, and eventually maximize its induction of mitochondrial dysfunction and therapeutically antifibrotic efficacy. The prepared sorafenib complex micelles not only exhibited a suitable particle size, uniform morphology, and nice stability, but also performed excellently in the biosafety and HSCs-targetability in vitro and in vivo. In human active HSC cell lines, they markedly attenuated mitochondrial hyperactivity, induced apoptosis, and downregulated fibrosis markers as expected; while in a CCl₄-induced murine model of hepatic fibrosis, they effectively restricted the expansion of MF-HSCs, reduced collagen deposition, and promoted the healing of liver damage, showing a good potential in fibrosis curation. Collectively, our VPP/TPGS complex micelles provide an ideal drug delivery platform that has the potential to revolutionize the treatment of liver fibrosis via addressing its cellular and metabolic underpinnings and thus improve patient outcomes.

肝纤维化是一种病理状态，其特征是细胞外基质的过度积累，主要是由静止的肝星状细胞（hsc）向肌成纤维细胞（MF）表型的转化及其导致的过度扩张引起的。活化的造血干细胞完全依靠其过度活跃的线粒体提供能量和生物量，以实现其快速增殖和胶原分泌，因此针对其线粒体的干预可以有效地限制其病理扩增和对肝纤维化的贡献。在这里，我们尝试了索拉非尼，一种通过诱导线粒体功能的破坏和丧失来发挥抗癌作用的药物，以达到抗纤维化的目标。为了克服索拉非尼在生物利用度、毒性和细胞内停留等方面的应用局限性，最终最大限度地发挥其诱导线粒体功能障碍和治疗性抗纤维化的功效，我们专门设计和制造了一个复杂的胶束系统VA-PEG-PCL/TPGS (VPP/TPGS)，将索拉非尼选择性地包裹和递送到活化的造血干细胞中。所制备的索拉非尼复合物胶束不仅粒径合适、形态均匀、稳定性好，而且在体外和体内均表现出良好的生物安全性和hsc靶向性。在人类活跃的HSC细胞系中，如预期的那样，它们显著减弱了线粒体的过度活性，诱导了细胞凋亡，并下调了纤维化标志物；而在ccl4诱导的小鼠肝纤维化模型中，它们有效地限制了mf - hsc的扩张，减少了胶原沉积，促进了肝损伤的愈合，在纤维化治疗中显示出良好的潜力。总的来说，我们的VPP/TPGS复合胶束提供了一个理想的药物输送平台，有可能通过解决肝纤维化的细胞和代谢基础来彻底改变肝纤维化的治疗，从而改善患者的预后。

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引用次数: 0

Using in-line measurement and statistical analyses to predict tablet properties compressed using a Styl’One compaction simulator: A high shear wet granulation study 使用在线测量和统计分析来预测使用Styl'One压实模拟器压缩的片剂性能：高剪切湿造粒研究。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125098

Issa Munu , Andrei L. Nicusan , Jason Crooks , Kendal Pitt , Christopher Windows-Yule , Andrew Ingram

High shear wet granulation (HSWG) is widely used in tablet manufacturing mainly because of its advantages in improving flowability, powder handling, process run time, size distribution, and preventing segregation. In-line process analytical technology measurements are essential in capturing detailed particle dynamics and presenting real-time data to uncover the complexity of the HSWG process and ultimately for process control. This study is to find relationships between Lenterra in-line measurements and granule properties and tablet properties. The Styl’One Evolution compaction simulator was used to produce tablets that mimic an industrial rotary tablet press, which is different from the Gamlen used in our previous study. Furthermore, this research provided an understanding of the granule growth mechanisms during the granulation process, revealing that an induction granule growth mechanism occurs. This is specific to the material and process conditions studied. The model developed using data from a Gamlen tabletting press demonstrated high predictability for data generated using the Styl’One Evolution compaction simulator, with an R² value of 0.9535 and a RMSE of 0.4040 MPa. This finding highlights the ability of the model to predict tablet tensile strength independently of the compaction machine used, suggesting industrial-scale applications. The findings of this research provide substantial advances in understanding and monitoring the granulation process, with promising implications for scalable industrial processes.

高剪切湿造粒（HSWG）广泛应用于片剂生产，主要是因为它在改善流动性、粉末处理、工艺运行时间、粒度分布和防止离析方面的优势。在线过程分析技术测量对于捕获详细的颗粒动力学和呈现实时数据以揭示HSWG过程的复杂性并最终实现过程控制至关重要。本研究旨在寻找Lenterra在线测量与颗粒性质和片剂性质之间的关系。Styl'One Evolution压实模拟器用于模拟工业旋转压片机来生产药片，这与我们之前研究中使用的Gamlen压片机不同。此外，本研究还揭示了造粒过程中颗粒的生长机制，揭示了诱导颗粒生长机制。这是特定于所研究的材料和工艺条件。利用Gamlen压片机数据开发的模型对style 'One Evolution压实模拟器生成的数据具有较高的可预测性，R2值为0.9535，RMSE为0.4040 MPa。这一发现强调了该模型独立于所使用的压实机预测片剂抗拉强度的能力，这表明了工业规模的应用。本研究的发现为理解和监测造粒过程提供了实质性的进展，对可扩展的工业过程有希望的影响。

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引用次数: 0

Bromocriptine mesylate-loaded nanoparticles co-modified with low molecular weight protamine and lactoferrin for enhanced nose-to-brain delivery in Parkinson’s disease treatment 载溴隐肽甲磺酸纳米颗粒与低分子量鱼精蛋白和乳铁蛋白共修饰，用于增强帕金森病治疗中的鼻至脑递送。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125054

Huijing Cong , Jing Hu , Jing Wang, Baiyu Chang, Rongtao Li, Xinran Cui, Chenghao Zhang, Hongyu Ji, Congcong Lin, Jingling Tang, Jiaxin Liu

Parkinson’s disease confronts challenges in drug delivery due to the blood-brain barrier. Intranasal delivery bypasses the blood-brain barrier for improved drug bioavailability, yet narrow nasal space and brief retention time hinder clinical applicability. We conducted a Bromocriptine Mesylate-loaded PLGA nanoparticles co-modified with low molecular weight protamine (LMWP) and lactoferrin (Lf) (LMWP/Lf-BCM-NPs) for nose-to-brain delivery. The resulting LMWP/Lf-BCM-NPs were uniform spheres with an average size of 248.53 ± 16.25 nm and zeta potential of −2.63 ± 0.74 mV. Fourier transform infrared spectroscopy confirmed LMWP and Lf attachment. The co-modified nanoparticles showed improving cellular transport and good viability. The LMWP/Lf-BCM-NPs showed increased brain targeting efficiency in mice. In haloperidol-induced Parkinson mouse models, the LMWP/Lf-BCM-NPs showed increased brain targeting efficiency, enhanced behavioral regulatory effects, enhanced antioxidant effects and neuroprotection effects. This study paves the way for a novel, non-invasive brain-targeted therapy, offering a promising avenue for Parkinson’s disease clinical treatment.

由于血脑屏障的存在，帕金森病在给药方面面临挑战。经鼻给药可绕过血脑屏障提高药物的生物利用度，但狭窄的鼻腔空间和短暂的保留时间阻碍了临床应用。研究人员利用低分子量鱼精蛋白（LMWP）和乳铁蛋白（Lf）（LMWP/Lf- bcm - nps）共修饰了溴隐肽甲磺酸负载的PLGA纳米颗粒，用于鼻至脑递送。所得LMWP/Lf-BCM-NPs为均匀球形，平均粒径为248.53 ± 16.25 nm， Zeta电位为-2.63 ± 0.74 mV。傅里叶变换红外光谱证实了LMWP和Lf的附着。共修饰的纳米颗粒具有改善细胞运输和良好的生存能力。LMWP/Lf-BCM-NPs在小鼠中显示出更高的脑靶向效率。在氟哌啶醇诱导的帕金森小鼠模型中，LMWP/Lf-BCM-NPs表现出更高的脑靶向效率，增强的行为调节作用，增强的抗氧化作用和神经保护作用。这项研究为一种新的、非侵入性的脑靶向治疗铺平了道路，为帕金森病的临床治疗提供了一条有希望的途径。

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引用次数: 0

High AIPH-Loaded Infinite coordination Polymers nanoparticles for long-term thermodynamic-chemo cascade tumor synergistic therapy 高aiph负载无限配位聚合物纳米颗粒用于长期热化学级联肿瘤协同治疗。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125092

Shuai Zhang , Rong Wang , Yuanyuan Ji , Zhidong Wang , Hong Wu , Yan Li , Shuo Zhang , Siyuan Luo , Chenyu Zhao , Jingran Di , Daocheng Wu

To enhance the tumor thermodynamic-chemo synergistic therapy efficacy, high loading of AIPH-Cu(II)-AQ4N Infinite Coordination Polymer nanoparticles (ICP NPs) were developed, which have high AIPH loading of 44.5 %, thermal stability, pH responsive release all therapeutic agents in the tumor tissue and lower toxicity. A long-term thermodynamic-chemo cascade tumor synergistic therapy strategy was developed with these nanoparticles. It is found ICP NPs exhibit diameters of 115.8 ± 23.7 nm, a substantial fraction of AQ4N and less 40 % of AIPH is released from ICP NPs within 70 h at pH 4.0–5.0, while the release rates of AQ4N and AIPH from ICP NPs over 72 h almost no release in normal tissues. A long-term two-stage therapeutic cascade procedure assisted by electrothermal was carried out, in which sufficient amount of AIPH maintain thermodynamic therapy 10 min at first stage and thermodynamic-chemo synergistic therapy 72 h at second stage. Under this procedure, the resulting nanoparticles demonstrate the powerful comprehensive therapeutic outcomes, small tumor entire eliminated and there is no recurrence for 60 days. Even for large tumors, the tumor inhibition rate is as high as 90 % at 16 days using lower drug dosage. This study offers remarkable potential for tumor cascade synergistic therapy in future.

为了提高肿瘤热化疗协同治疗效果，研制了高负载AIPH- cu (II)-AQ4N无限配位聚合物纳米颗粒（ICP NPs），该纳米颗粒AIPH负载高达44.5 %，热稳定性好，pH响应释放肿瘤组织中所有治疗剂，毒性低。利用这些纳米颗粒开发了一种长期的热力学-化学级联肿瘤协同治疗策略。结果表明，ICP NPs的直径为115.8 ± 23.7 nm，在pH 4.0 ~ 5.0条件下，ICP NPs在70 h内释放了大部分AQ4N和不到40% %的AIPH，而在72 h以上的ICP NPs中，AQ4N和AIPH的释放率几乎没有释放。在电热辅助下进行了长期的两阶段治疗级联程序，其中足够量的AIPH在第一阶段维持热力学治疗10 min，在第二阶段维持热力学化疗协同治疗72 h。在这个过程中，产生的纳米颗粒显示出强大的综合治疗效果，小肿瘤完全消除，60 天内没有复发。即使对于较大的肿瘤，使用较低的药物剂量，在16 天肿瘤抑制率高达90 %。该研究为今后的肿瘤级联协同治疗提供了显著的潜力。

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引用次数: 0

Harnessing phytoconstituents in ethosomes: A new frontier in skin disorder management

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2025.125273

Meghna Chauhan , Jyoti Chandra , Garima Gupta , Ramasubbamma Ramaiah , Umme Hani , Prashant Kesharwani

The rising incidence of skin disorders has necessitated the exploration of innovative therapeutic modalities that harness the beneficial properties of natural compounds. Phytoconstituents, renowned for their diverse pharmacological attributes, present considerable promise in the management of various dermatological conditions. This review delineates the integration of phytoconstituents into ethosomal formulations, which are advanced lipid-based carriers specifically designed to enhance transdermal delivery. We discuss the advantages conferred by ethosomes, including their capacity to improve the stability and bioavailability of phytochemicals, facilitate deeper skin penetration, and provide controlled release profiles. Recent advancements in the formulation of ethosomes encapsulating a variety of phytoconstituents are highlighted, with a focus on their physicochemical properties, therapeutic efficacy, and safety profiles. Furthermore, the review examines the mechanisms by which ethosomes enhance the delivery of bioactive compounds to targeted skin layers, particularly in the context of treating conditions such as acne, eczema, and psoriasis. Challenges associated with formulation stability and scalability are also addressed, along with potential future research directions in this domain. By synthesizing current knowledge and identifying existing gaps, this article aims to provide a comprehensive overview of phytoconstituent-based ethosomes as a promising strategy for the development of effective and safe topical therapies for skin disorders. Ultimately, this review underscores the potential of these innovative formulations to improve patient outcomes and contribute significantly to the advancement of dermatological treatment options.

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引用次数: 0

ROS-responsive quercetin-based polydopamine nanoparticles for targeting ischemic stroke by attenuating oxidative stress and neuroinflammation 基于槲皮素的多巴胺纳米粒子对氧化应激和神经炎症的抑制作用可用于治疗缺血性中风。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-01-25 DOI: 10.1016/j.ijpharm.2024.125087

Chuyao Jian , Yigen Hong , Hongsheng Liu , Qinglu Yang , Shaofeng Zhao

Ischemic stroke (IS), a prevalent cerebrovascular disorder, is characterized by high morbidity rates and significant disability. However, relevant drug therapy for IS still suffers from limitations such as limited blood–brain barrier (BBB) penetration efficiency, single therapeutic target, short half-life, and strong side effects. The development of multi-target neuroprotective agents using natural drug molecules with low toxicity and combining them with nanotechnology to improve BBB permeability and drug utilization is an important direction in the development of IS therapeutic strategies. Based on the anti-inflammatory and antioxidant properties of quercetin (Que), as well as the ROS-responsive degradation properties of polydopamine (PDA), an IS therapeutic strategy (Que@DAR NPs) was developed in this study. Que@DAR NPs were formed by dopamine wrapping Que by oxidative self-assembly and wrapping the rabies virus glycoprotein (RVG29) on the surface. The results showed that Que@DAR NPs greatly improved the dispersion stability of Que and exhibited ROS-responsive degradation properties. Cellular internalization assay in human neuroblastoma cells (SH-SY5Y) showed that RVG29 peptide substantially augmented the cellular uptake of Que@DAR NPs. Moreover, Que@DAR NPs can effectively reduce the oxidative damage of SH-SY5Y cells and induce the polarization of microglia to anti-inflammatory (M2) phenotype. In vivo studies further demonstrated that Que@DAR NPs inhibited neuroinflammation, reduced neuronal apoptosis, and significantly ameliorated neurological dysfunction in a rat model of middle cerebral artery occlusion (MCAO). In conclusion, Que@DAR NPs provide a safe and effective new strategy for the precision treatment of IS.

缺血性脑卒中（IS）是一种常见的脑血管疾病，具有发病率高、致残率高的特点。然而，针对缺血性脑卒中的相关药物治疗仍存在局限性，如血脑屏障（BBB）穿透效率有限、治疗靶点单一、半衰期短、副作用大等。利用低毒性的天然药物分子开发多靶点神经保护剂，并结合纳米技术提高 BBB 的通透性和药物利用率，是 IS 治疗策略发展的重要方向。本研究基于槲皮素（Que）的抗炎和抗氧化特性以及多巴胺（PDA）的ROS响应降解特性，开发了一种IS治疗策略（Que@DAR NPs）。Que@DAR NPs由多巴胺通过氧化自组装包裹Que并在其表面包裹狂犬病毒糖蛋白（RVG29）形成。结果表明，Que@DAR NPs大大提高了Que的分散稳定性，并表现出ROS响应的降解特性。在人神经母细胞瘤细胞（SH-SY5Y）中进行的细胞内化试验表明，RVG29 肽大大提高了细胞对 Que@DAR NPs 的吸收。此外，Que@DAR NPs 还能有效减轻 SH-SY5Y 细胞的氧化损伤，并诱导小胶质细胞极化为抗炎（M2）表型。体内研究进一步证明，在大脑中动脉闭塞（MCAO）大鼠模型中，Que@DAR NPs能抑制神经炎症，减少神经元凋亡，并显著改善神经功能障碍。总之，Que@DAR NPs为IS的精准治疗提供了一种安全有效的新策略。

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